Integrated molecular characterization of pediatric soft tissue sarcomas: A report from the COG and CCDI molecular characterization initiative.

The Molecular Characterization Initiative (MCI), a partnership between the Children’s Oncology Group (COG) and the NCI’s Childhood Cancer Data Initiative (CCDI), provides standardized genomic profiling of tumors and germline for subjects with newly diagnosed pediatric soft tissue sarcomas (STS). Here, we report on STS patients <25 years enrolled in MCI from July 2022 to July 2023. MCI enrollment was offered to COG institutions through APEC14B1 (Project: EveryChild), enabling patient consent, collection of clinical data, and submission of tissue/blood samples. Bio-pathology Center centrally managed sample processing, quality control, and nucleotide extraction, while molecular assays were performed at Nationwide Children’s Hospital’s Institute for Genomic Medicine. Whole-exome sequencing (WES) of tumor/normal, DNA methylation arrays and RNA fusion analysis were conducted in a CLIA-certified environment. Clinical reports, except methylation results, were returned to treating institutions within 21 days, and clinical, sequencing and methylation data were deposited in NCI’s Cancer Data Service. In total, 226 rhabdomyosarcoma (RMS),158 non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), and 36 non-malignant soft tissue tumors (21 desmoid tumors) from 129 institutions were enrolled. Of 172 RMS patients, 56 were fusion-positive (FP) (46 with fusion and 10 with fusions of other genes). WES of 179 RMS patients identified somatic mutations in 33 genes in 110 patients (61.4%). Most frequently mutated genes included [25/179,14%; FN (fusion-negative) RMS:21%, FP RMS:2%), (21/179,12%; FN RMS:15%, FP RMS: 7%), and (18/179, 10%; FN RMS:14%, FP RMS: 3%). Somatic copy number variants (CNVs) were detected in 164/179 (92%) of RMS patients. Germline variants were identified in 18 of 179 RMS (10%; FN RMS:15%, FP RMS: 2%); and most commonly germline altered genes included (4/179, 2%), (2/18, 1%), and (2/179,1%). Among 158 NRSTS > 20 histologies were enrolled, most common being synovial sarcoma (n = 16, 8%). Of 49 patients with an initial diagnosis of undifferentiated sarcoma, round cell sarcoma, spindle cell sarcoma and sarcoma NOS, 32 underwent fusion testing, and 28 had WES: in 13 (40%) sequencing resulted in specific diagnosis [CIC::DUX4 in 5, BCOR::CCNB3 in 4, rearrangement in 2, SS18::SSX2 in 1 and EWSR1::ETV1 in 1], and 5 (15%) had rare fusions involving , , and genes;16 exhibited somatic CNVs; 5(18%) had somatic mutations; and 2 (7%) carried germline variants in and genes. Overall, MCI results, as reported by institutions, facilitated clinical trial enrollment in 15%, receipt of targeted therapy outside trials in 17%, and diagnostic refinement in 25% of tested patients, respectively. CCDI’s MCI program provides comprehensive genomic profiling of pediatric and adolescent STS, uncovering distinct somatic genetic alterations, rare fusions, actionable genomic targets and germline variants.

Duke Scholars

Author Corinne Mary Linardic Pediatrics, Hematology-Oncology